Acylation by an ester

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

All the erythrophleum alkaloids examined in detail so far are of the same type, viz., acyl esters of either monomethylaminoethanol, e.g., erythrophleine and coumingidine or dimethylaminoethanol, such as cassaine or cassaidine. The acyl substituents are complex, yield 1 7 8-trimethylphenanthrene on selenium dehydrogenation, and contain at least one hydroxyl group, which may be acylated by an aliphatic acid, e.g., coumingine forms three components on hydrolysis. 

An interesting rearrangement which is based on the intramolecular acylation of an enamine by an ester is found in the aromatization of the adduct derived from N-methylpyrrole and an acetylenedicarboxylic ester (407,408). 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

Acylation of the dianion of ethyl acetoacetate by an ester is a useful addition to this area of pyranone synthesis. In this reaction and in the formation of the trianions of 2,4,6-triketones the use of lithium diisopropylamide as the base is valuable (76JA7733). The triketo acid from the trianion cyclizes in mineral acids to the pyran-4-one, but in acetic anhydride the pyran-2-one is formed (Scheme 101) (71JA2506). 

A Claisen condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in equilibrium with the ester (cf. Table 13.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 13.57 for the example of the condensation of ethyl butyrate. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 13.57) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of ethyl butyrate and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

Enolate D of Figure 13.74 is acylated by the ester following the usual mechanism. The bicyclic compound A is a product, which contains a new six-membered ring that has been annulated to an existing ring. 

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

Fig. 2. Schematic diagram of the catalytic mechanism of 20S proteasomes. A proton transfer from the hydroxyl group of Thrl of /3 subunits to its own terminal amino group initiates the nucleophilic attack (I). As a result of the nucleophilic addition to the carbonyl carbon of the scissile peptide bond, a tetrahedral intermediate is formed (II). By an N—O acyl rearrangement, an ester is formed (the acyl enzyme) and the amino-terminal cleavage product is released (III). Finally, hydrolysis of the acyl enzyme yields the carboxyl-terminal cleavage product and frees the enzyme for another reaction cycle (IV).

Hydroxylamine is acylated by carboxylic esters, giving hydroxamic acids. The reaction often occurs in a few hours at room temperature if the components are mixed in alcoholic solution, preferably with addition of an equivalent of an alkoxide. In the latter case the hydroxamic acids are obtained as salts, but are easily liberated therefrom. 

N-acylated by an a-halo-acid, give rise to epoxy-esters [e.g. (119)]... 

The well established alkylation of phosphorylated benzyl carbanions has been complemented by the arylation of purely alkyl species. Thus, diethyl (chloromethyl)phosphonate reacts with aryllithium reagents to give the diethyl esters of benzylic phosphonic acids The alternative procedure has been adopted in a synthetic route to isoprenyl (phos-phinylmethyl)phosphonates. Here, a lithiated dialkyl alkylphosphonate is acylated using an ester of the phosphonochloridic acid, R P(0)(0H)C1, where R is an isoprenoid residue. The acylation process has also been carried to with (R0)2P(0)C1 or (Me2N)2P(0)Cl ... 

The carnitine profile quantifies the amount of carnitine present (total carnitine) as well as the carnitine that is free or bound by an ester link to acyl-CoA (acyl or esterified carnitine) (Box 8.2). 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

Hauser and co-workers have prepared a number of triketones by (1) acylation of benzoylacetone with aliphatic esters employing lithium amide, (2) by twofold aroylation of acetone with methyl esters using sodium hydride, (3) by aroylation and acylation of aliphatic diketones with potassium amide in liquid ammonia and (4) by aroylation of sodioacetoacetaldehyde in the presence of potassium amide. Disodio- and dipotassiobenzoylacetone are not acylated by ethyl acetate or by phenyl propionate. However, dilithiobenzoylacetone and dilithioacetylacetone with an excess of lithium amide are acylated by aliphatic esters. It is usually more convenient to synthesize 4-pyridones directly from these triketones by cyclization with ethanolic ammonia rather than by way of the intermediate Qpyrone. ... 

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